6342 Langmuir 2007, 23, 6342-6351

Core-Shell Magnetite Nanoparticles Surface Encapsulated with Smart

Stimuli-Responsive Polymer: Synthesis, Characterization, and LCST
of Viable Drug-Targeting Delivery System
J. L. Zhang,† R. S. Srivastava,§ and R. D. K. Misra*,†
Center for Structural and Functional Materials and Department of Chemical Engineering, UniVersity of
Louisiana at Lafayette, P.O. Box 44130, and Department of Chemistry, UniVersity of Louisiana at
Lafayette, P.O. Box 44370, Lafayette, Louisiana 70504

ReceiVed December 14, 2006. In Final Form: March 20, 2007

We describe here the synthesis of a novel magnetic drug-targeting carrier characterized by a core-shell structure.
The core-shell carrier combines the advantages of a magnetic core and the stimuli-responsive property of the
thermosensitive biodegradable polymer shell (e.g., an on-off mechanism responsive to external temperature change).
The composite nanoparticles are ∼8 nm in diameter with ∼3 nm shell. The lower critical solution temperature (LCST)
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is ∼38 °C as determined by UV-vis absorption spectroscopy. The carrier is composed of cross-linked dextran grafted
with a poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [dextran-g-poly(NIPAAm-co-DMAAm)] shell and
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superparamagnetic Fe3O4 core. Fourier transform infrared spectroscopy (FTIR) confirmed the composition of the
carrier. The synthesized magnetic carrier system has potential applications in magnetic drug-targeting delivery and
magnetic resonance imaging.

Introduction
In recent years, the usage of magnetic nanoparticles has
attracted significant interest in biomedicine and biomedical
engineering for applications including magnetic carriers for drug
delivery systems and contrast enhancement agents in magnetic
resonance imaging (MRI) for diagnostics. The motivation for
the use of magnetic nanoparticles is related to their superpara-
magnetic characteristics, higher saturation magnetization, and
good biocompatibility.1-3 Superparamagnetic nanoferrites ex-
hibiting higher magnetization and good biocompatibility can be
appropriately used as magnetic drug-targeting carriers for
hyperthermia,4-8 controlled drug release,9-11 and as contrast
enhancement agents in MRI.12-14 An important attribute of
superparamagnetic nanoparticles is that magnetism is not retained
upon removal of the applied external magnetic field. Additionally,
* dmisra@louisiana.edu.
† Center for Structural and Functional Materials and Department of
Chemical Engineering.
§ Department of Chemistry.
(1) Ito, A.; Shinkai, M.; Honda, H.; Kobayashi, T. J. Biosci. Bioeng. 2005,
100, 1.
(2) Guptaa, A. K.; Gupta, M. Biomaterials 2005, 26, 3995.
(3) Sunderland, C. J.; Steiert, M.; Talmadge, J. E.; Derfus, A. M.; Barry, S.
E. Drug DeV. Res. 2006, 67, 70.
(4) Jordan, A.; Scholz, R.; Wust, P.; Hling, H. F.; Felix, R. J. Magn. Magn.
Mater. 1999, 201, 413.
(5) Babincová, M.; Leszczynska, D.; Sourivong, P.; Ĉiĉmanec, P.; Babinec,
P. J. Magn. Magn. Mater. 2001, 225, 109.
(6) Jordan, A.; Scholz, R.; Klaus, M. H.; Johannsen, M.; Wust, P.; Nadobny,
J.; Schirra, H.; Schmidt, H.; Deger, S.; Loening, S.; Lanksch, W.; Felix, R. J.
Magn. Magn. Mater. 2001, 225, 118.
(7) Moroz, P.; Jones, S. K.; Winter, J.; Bruce, N. J. Surg. Oncol. 2001, 78,
22.
(8) Kong, G.; Braun, R. D.; Dewhirst, M. W. Cancer Res. 2001, 61, 3027.
(9) Detlef, M. S.; Thomas, S. R. J. Magn. Magn. Mater. 2006, 302, 267.
(10) Sonvico, F.; Mornet, S.; Vasseur, S.; Dubernet, C.; Jaillard, D.; Degrouard,
J.; Hoebeke, J.; Duguet, E.; Colombo, P.; Couvreur, P. Bioconjugate Chem. 2005,
16, 1181.
(11) Jain, T. K.; Morales, M. A.; Sahoo, S. K.; Leslie-Pelecky, D. L.;
Labhasetwar, V. Mol. Pharm. 2005, 2, 194.
(12) Kohler, N.; Sun, C.; Wang, J.; Zhang, M. Langmuir 2005, 21, 8858.
(13) Kangarlu, A.; Ibrahim, T. S.; Shellock, F. G. Magn. Reson. Imaging 2005,
23, 53.
(14) Mulder, W. J. M.; Strijkers, G. J.; van Tilborg, G. A. F.; Griffioen, A.
W.; Nicolay, K. NMR Biomed. 2006, 19, 142.
the ability to control the size range of nanoparticles from a few
nanometers up to tens of nanometers makes them comparable
to a virus (20-450 nm), a protein (5-50 nm), or a gene (2 nm
wide and 10-100 nm long),15 enabling them to be in close
proximity to a biological entity of interest.
In spite of the above advantages, there is a need to functionalize
nanoparticles with a polymer for applications involving drug
delivery systems and MRI, in the absence of which they will
tend to aggregate and have short blood half-life in circulation.2
Agglomeration of nanoparticles with large surface-to-volume
ratio will result in the loss of magnetic characteristics, decrease
of surface activity, and rapid elimination by macrophages or the
reticular endothelial system (RES) before they actually arrive at
the target cells. Also, these drawbacks prevent effective loading
of drug or cell-labeling molecules.16,17 In view of the afore-
mentioned reasons, it is desired that the magnetic nanoparticles
are encapsulated with a polymer shell with the magnetic
nanoparticles as the core. Adopting a core-shell structure, besides
preventing agglomeration of nanoparticles and cleaning of
macrophages or RES, additionally provides novel properties that
are suitable for biological applications such as biocompatibility,
drug-loading ability, and controlled drug release.18 It is envisaged
that the surface-modified nanoparticles can be used as contrast
enhancement agents and magnetic drug-targeting carriers,
enabling the response of drug release to be monitored over time
during treatment, for instance, in the case of cancer,1 where
site-specific treatment is preferred to avoid side effects and
toxicity.
In general, for functionalization of magnetic nanoparticles,
inorganic materials (e.g., silica, gold), polymers (e.g., poly-
(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(lactic-
(15) Pankhurst, Q. A.; Connolly, J.; Jones, S. K.; Dobson, J. J. Phys. D: Appl.
Phys. 2003, 36, R167.
(16) Neuberger, T.; Schöpf, B.; Hofmann, H.; Hofmann, M.; von Rechenberg,
B. J. Magn. Magn. Mater. 2005, 293, 483.
(17) Rana, S.; Gallo, A.; Srivastava, R. S.; Misra, R. D. K. Acta Biomater.
2007, 3, 233.
(18) Kohler, N.; Fryxell, G. E.; Zhang, M. Q. J. Am. Chem. Soc. 2004, 126,
7206.

10.1021/la0636199 CCC: $37.00 © 2007 American Chemical Society

Published on Web 04/27/2007
Encapsulated Core-Shell Nanoparticles
co-glycolic acid) (PLGA)), surfactants (e.g., oleic acid, sodium
oleate, dodecylamine), biomolecules (e.g., dextran, chitosan) can
be considered.2 However, in recent years, thermosensitive
polymers are being considered to enhance drug-loading ability
and controlling drug release because of the large inner volume
and ability to manipulate permeability, and more importantly,
they can respond to the external stimulus with an on-off switch
mechanism.19-21 In this regard, liposomes with biocompatibility
and poly(N-isopropylacrylamide) (PNIPAAm)-based polymers
are two potential temperature-responsive materials. Liposomes
are characterized by a concentric bilayered vesicle structure
consisting of amphiphilic phospholipids that surround an aqueous
core and can be utilized for loading drugs and magnetic
nanoparticles. The size of liposomes is in the range 0.025-10
µm in diameter and can be designed with desired size and
morphology through process and composition modification.22
On heating, phospholipid bilayers exhibit an endothermic
transition at a specific temperature (Tc), which is lower than the
melting point. Below the Tc, the phospholipid bilayers are
characterized by a gel state, and above the Tc, they are in a liquid
crystalline state.23 In the past two decades, there has been
significant progress in the use of liposome-mediated delivery of
therapeutic agents from the laboratory to the clinic.24,25 However,
one of the drawbacks with targeted liposomes is that the processing
of synthetic liposomes is complex and involves high cost, while
the natural liposomes do not have a defined phase transformation
temperature. In view of this disadvantage, their usage has been
limited.
The PNIPAAm homopolymer is a synthetic thermosensitive
polymer with a lower critical solution temperature (LCST) of
32 °C in water. In aqueous solution, it is hydrated and expands
below the LCST, while it is hydrophobic and collapsed at
temperatures greater than the LCST. This implies that it
experiences a sharp coil-globule transition in water at the LCST,
transforming from a hydrophilic state below the LCST to a
hydrophobic state above the LCST.26,27 This behavior is attributed
to the fact that, at temperatures lower than the LCST, the
predominantly intermolecular hydrogen bonding between the
PNIPAAm chains and water molecules results in the PNIPAAm
chains adopting a water-soluble coiled structure, while above
the LCST, intermolecular hydrogen bonding between CdO and
NsH groups in the PNIPAAm chains makes the chains adopt
a compact and collapsible structure, decreasing their water
solubility.26,27 The LCST of PNIPAAm can be effectively
controlled by incorporating hydrophilic charged units, such as
methacrylic acid (MAA), as well as hydrophobic units, such as
butyl methacrylate. Generally, the hydrophilic charged residues
tend to increase the LCST, while hydrophobic residues tend to
lower the LCST.28,29 The LCST of the PNIPAAm copolymer
(19) Lai, C. Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija,
S.; Lin, V. S.-Y. J. Am. Chem. Soc. 2003, 125, 4451.
(20) Giri, S.; Trewyn, B. G.; Stellmaker, M. P.; Lin, V. S.-Y. Angew. Chem.,
Int. Ed. 2005, 44, 5038.
(21) Zhu, Y.; Shi, J.; Shen, W.; Dong, X.; Feng, J.; Ruan, M.; Li, Y. Angew.
Chem., Int. Ed. 2005, 44, 5083.
(22) Kono, K. AdV. Drug DeliVery ReV. 2001, 53, 307.
(23) Zhang, L. F.; Granick, S. Nano Lett. 2006, 6, 694.
(24) Roux, E.; Lafleur, M.; Lataste, EÄ .; Moreau, P.; Leroux, J-C. Biomac-
romolecules 2003, 4, 240.
(25) Bos, C.; Lepetit-Coiffé, M.; Quesson, B.; Moonen, C. T. W. Magn. Reson.
Med. 2005, 54, 1020.
(26) Alarcón, C. D. L. H.; Pennadam, S.; Alexander, C. Chem. Soc. ReV. 2005,
34, 276.
(27) Twaites, B.; Alarcón, C., de las, H.; Alexander, C. J. Mater. Chem. 2005,
15, 441.
(28) You, Y. Z.; Hong, C. Y.; Pan, C. Y.; Wang, P. H. AdV. Mater. 2004, 16,
1953.
(29) Uludag, H.; Norrie, B.; Kousinioris, N.; Gao, T. Biotechnol. Bioeng.
2001, 73, 510.
Langmuir, Vol. 23, No. 11, 2007 6343
can be tuned to be above the body temperature by incorporating
comonomer units, such as N,N-isopropylacrylamide, rendering
PNIPAAm-based materials as potential candidates for drug
delivery applications. If we can control the LCST such that it
is greater than the body temperature by a suitable external
stimulus, then the mechanism can be utilized for the drug-
controlled release systems. However, the disadvantage is that
the PNIPAAm homopolymer is not biodegradable.
More recently, the LCST and enzymatic degradation of dextran-
g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [dex-
tran-g-poly(NIPAAm-co-DMAAm)] have been studied.30 The
grafted copolymers in phosphate buffer solution (PBS) exhibited
an LCST of ∼40 °C because of the thermosensitive nature of
the grafted polymer. Also, the water-soluble dextran as the main
chain was biodegradable, and the degradation increased with a
decrease in the graft length below the LCST, while enzymatic
degradation was independent of the graft length above the LCST.
This “smart” behavior and enzymatic degradation is particularly
attractive in controlled drug delivery and biomedical applications.
The specific and controlled delivery of drugs to the target site
is essential to increase their effectiveness and performance,
decrease side effects on healthy tissues, and promote the rate of
action.
Thus, combining the stimuli-responsive “smart” behavior and
enzymatic degradation of the biopolymers with properties of
magnetic nanoparticles is a viable approach to fabricate a drug
carrier. This system will serve as an “effective drug delivery
system with targeting and controlled drug release”. The objective
of the work presented here is to describe the synthesis of a new
and novel drug-targeting delivery system that innovatively
combines the stimuli-responsive property of the thermosensitive
biodegradable polymer with the advantages of magnetic nano-
particles to develop a core-shell structure with a triggered release
mechanism. To our understanding, such a smart system is being
proposed for the first time. Monodisperse magnetic Fe3O4
nanoparticles constituting the core are encapsulated with the
thermosensitive biodegradable polymers as a drug carrier. The
magnetic drug-targeting carrier has the following advantages:
(a) the LCST of a given polymer can be controlled above human
body temperature by incorporation of comonomer units of
N-isopropylacrylamide; (b) the magnetic drug carrier can be
targeted to a selected site through the use of external magnetic
field, and the encapsulated drug can be subsequently released
from the thermosensitive biodegradable polymer in response to
heat generated from an alternative magnetic field; and (c) the
drug carrier is biodegradable.
Experimental Section
Materials. The chemicals used for the synthesis of the core-
shell nanoparticle system were iron(III) acetylacetonate (Fe(acac)3)
(99.9%), 1,2-dodecanediol (g90%), oleic acid (cis-9-octadecenoic
acid 90%), oleylamine (cis-1-aminooctadecene >70%), diphenyl
ether (99%), absolute ethanol, hexane, tetrahydrofuran (g99%),
tetramethylammonium hydroxide (25%) in methanol, 11-aminoun-
decanoic acid (99%), and dichloromethane (99%). N,N-Dimethy-
lacrylamide (DMAAm, 99%) was purified by vacuum distillation
at 82 °C/20 mmHg. N-Isopropylacrylamide (NIPAAm, 97%), methyl
3-mercaptopropionate (g98.0%), 2 2′-azobisisobutyronitrile (AIBN,
98%), methanol (99.9%), diethyl ether (99.9%), hydrazine mono-
hydrate (g98.0%), dialysis membrane (MWCO e 1200), dextran
(Mn ) 10 000 from BioWorld-Serving Life-Sciences and Biotech-
nology Industries Worldwide, USA), dimethylaminopyridine (DMAP,
g99%), and dimethyl sulfoxide (DMSO, g99.5%) were purchased
(30) Huh, K. M.; Kumashiro, Y.; Ooya, T.; Yui, N. Polym. J. 2001, 33,
108.
6344 Langmuir, Vol. 23, No. 11, 2007
from Sigma-Aldrich, except as indicated, and used as received without
further purification. Pyridine (g99.0%) was dried over CaH2 (90-
95%) and distilled after refluxing for 3 h. 4-Nitrophenyl chloroformate
(97%), 1,6-hexamethylenediamine (99.0%), dialysis membrane (MW
) 12 400) were also purchased from Sigma-Aldrich and used as
received.
Preparation of Magnetite Nanoparticles. Fe3O4 nanoparticles
with an average diameter of 5 nm were prepared using the approach
of high-temperature decomposition proposed by Sun.31 First, 20 mL
of biphenyl ether, 0.71 g (2 mmol) of iron(III) acetylacetonate, 2.25
g (10 mmol) of 1,2-dodecanediol, 2.12 mL (6 mmol) of oleic acid,
and 2.19 mL (6 mmol) of oleylamine were mixed in a 150 mL
three-necked flask while magnetically stirring. The solution was
gradually heated to 200 °C under nitrogen atmosphere for 2 h. After
2 h, the nitrogen flow was stopped, and the solution was heated at
∼260 °C for 1 h to reflux. During this process, the initial brown-
black color of the solution gradually changed to dark black, indicating
synthesis of the magnetite nanoparticles. Subsequently, the resultant
solution was cooled to room temperature, and 40 mL ethanol was
added to yield a black precipitate. The black Fe3O4 precipitate was
separated by centrifuging at 15 000 rpm for 30 min.
In order to purify the Fe3O4 nanoparticles and to prevent them
from aggregation, the following experimental steps were carried
out. The black precipitate was redispersed in 10 mL of hexane in
the presence of 50 µL of oleic acid and 50 µL of oleylamine to yield
a nontransparent homogeneous solution. The homogeneous solution
was again centrifuged at 6000 rpm for 10 min, and any particulate
residue was removed. The solution containing magnetic nanoparticles
was again precipitated with ethanol (20 mL), centrifuged at 10 000
rpm for 20 min, and redispersed in 10 mL of hexane and dried at
60 °C for 24 h. The as-synthesized Fe3O4 colloid in hexane is
hydrophobic and stable for nearly a year, while the dried Fe3O4
sample can be stable for several months.
The magnetic nanoparticles in biomedical application need to be
hydrophilic; the hydrophobic Fe3O4 nanoparticles in hexane were
transformed to hydrophilic Fe3O4 nanoparticles using a tetramethy-
lammonium 11-aminoundecanoate bipolar surfactant.31 Tetram-
ethylammonium 11-aminoundecanoate was prepared by titrating a
methanolic suspension of 11-aminoundecanoic acid with methanolic
tetramethylammonium hydroxide, evaporating the solvent under
reduced pressure, and recrystallizing in tetrahydrofuran. 15 mg of
tetramethylammonium 11-aminoundecanoate and 50 µL of the
hydrophobic Fe3O4 colloid in hexane were added in 2 mL of
dichloromethane (CH2Cl2). After the brown mixture was sonicated
for about 5 min, the Fe3O4 nanoparticles were precipitated. The
dichloromethane solvent was removed, and the Fe3O4 nanoparticles
were washed with water using a magnet drawing Fe3O4 nanoparticles.
In the end, the Fe3O4 nanoparticles were redispersed in 10 mL of
deionized water while sonicating to form a stable brown colloid.
These hydrophilic Fe3O4 nanoparticles in aqueous colloidal solution
were subsequently used for encapsulation or coating with a
biodegradable thermosensitive polymer.
Synthesis of Dextran Grafted with Poly(N-isopropylacryla-
mide-co-N,N-dimethylacrylamide) [dextran-g-poly(NIPAAm-co-
DMAAm)] Thermosensitive and Biodegradable Polymer (defined
as smart polymer). Dextran-g-poly(NIPAAm-co-DMAAm) was
synthesized using the following four steps30 summarized in Scheme
1. The first step is synthesis of the poly(NIPAAm-co-DMAAm)
with a methyl ester end group [STP-COOCH3]. The polymerization
reaction was carried out by free radical copolymerization using methyl
3-mercaptopropionate as a chain transfer agent. NIPAAm (4.10 g),
DMAAm (0.95 mL), methyl 3-mercaptopropionate (80 µL), and
2,2′-azobisisobutyronitrile (AIBN) (0.15 g) were dissolved in 50
mL of methanol and the solution bubbled with nitrogen gas for 30
min. After the polymerization reaction at 50 °C for 24 h with stirring,
the solution is concentrated and precipitated with excessive cold
diethyl ether. After filtration and drying at 50 °C, the final product,
STP-COOCH3, was obtained.
(31) Sun, S.; Zeng, H.; Robinson, D. B.; Raoux, S.; Rice, P. M.; Wang, S. X.;
Li, G. J. Am. Chem. Soc. 2004, 126, 273.
Zhang et al.
The second step involved transformation of STP-COOCH3 into
STP-NHNH2. The transformation reaction was performed through
a hydrazinolysis reaction. 40 mL of STP-COOCH3 methanol solution
was added dropwise to 10 mL of methanol solution containing
excessive hydrazine monohydrate with stirring, followed by refluxing
for 5 h. The product was precipitated in excess diethyl ether. Then,
it was dialyzed against water using a dialysis membrane (MWCO
e 1200) for 3 days and freeze-dried.
The third step was preparation of dextran with 4-nitrophenyl
chloroformate. The dextran was activated using 4-nitrophenyl
chloroformate in the catalysis of 4-dimethylaminopyridine (DMAP).
250 mL mixing solution of DMSO/pyridine (volume ratio 1/1)
containing dextran (1.0 g), 4-nitrophenyl chloroformate (4.35 g),
and DMAP (0.20 g) was held at 0 °C for 8 h. After precipitation
and washing with ethyl alcohol, the product was filtered and dried
at 50 °C.
The final step concerned synthesis of the dextran-g-poly(NIPAAm-
co-DMAAm). The graft copolymers were synthesized by a coupling
reaction between the 4-nitrophenyl chloroformate-activated dextran
and STP-NHNH2. 1.0 g of activated dextran and 0.76 g of STP-
NHNH2 are dissolved in 60 mL of DMSO and allow to react at room
temperature for 48 h. After precipitation in diethyl ether and drying
at 50 °C, the dried product was dialyzed (MW ) 12 400) against
deionized water for 3 days to remove unreacted STP-NHNH2 and
then freeze-dried.
Coating of Magnetic Nanoparticles with the Smart Polymer.
In the above aqueous colloid solution containing hydrophilic Fe3O4
nanoparticles, 10 mg of the dextran-g-poly(NIPAAm-co-DMAAm)
thermosensitive polymer and the desired amount of 1,6-diamino-
hexane as cross-linker were added under sonication for 1 h at ∼50
°C. Since the dextran-g-poly(NIPAAm-co-DMAAm) thermosen-
sitive polymer contains the active 4-nitrophenyl chlorofomate groups,
they can be cross-linked by 1,6-diaminohexane around the magnetic
core to form the core-shell structure. These Fe3O4 nanoparticles
encapsulated with biodegradable thermosensitive polymer were
dialyzed in deionized water for 24 h to remove unreacted molecules.
Characterization of Nanoparticles. To examine the morphology,
size range, and structure of the nanoparticles, the as-synthesized
Fe3O4 nanoparticles dispersed in hexane and smart polymer
encapsulated Fe3O4 nanoparticles dispersed in deionized water
were placed onto a carbon-coated copper grid followed by drying
in air. Transmission electron microscopy (TEM) studies were carried
out using a Hitachi H-7600 microscope at an accelerating voltage
of 100 kV in conjunction with selected area electron diffraction
(SAED).
Characterization of Polymers. To confirm the structure of
polymers and functionalization of nanoparticles with biodegradable,
FTIR spectra were recorded of samples in the 400-4000 cm-1 region
in the transmission mode using an FT/IR-480 spectrometer at 4
cm-1 resolution. The KBr compressed pellet method was adopted
for solid samples, and a dropped liquid method using two transparent
silicone glasses was used for liquid or solution samples.
Determination of LCST of the Smart Polymer. The LCST
behavior of samples was determined using a UV-vis spectropho-
tometer (Lauda Brinkmann, Germany) equipped with a model Ecoline
RE106 temperature controller. The change in transmittance as a
function of temperature was recorded using a 500 nm wavelength.
Results and Discussion
Characterization of the Hydrophobic Magnetite Nano-
particles. The transmission electron micrograph (TEM) of
hydrophobic magnetite nanoparticles and corresponding selected
area electron diffraction (SAED) pattern are presented in Figure
1. The TEM micrograph suggests that the hydrophobic nano-
particles are nearly spherical in shape. The monodisperse Fe3O4
nanoparticles shown in Figure 1a have a narrow particle size
distribution with the mean size of ∼5 nm. Figure 1b gives the
SAED pattern of the monodisperse Fe3O4 nanoparticles. The
indexing of the SAED pattern result, summarized in Table 1,
Encapsulated Core-Shell Nanoparticles Langmuir, Vol. 23, No. 11, 2007 6345

Scheme 1. Steps in the Synthesis of Dextran Grafted with Poly(NIPAAm-co-DMAAm) According to ref 30

indicates that the nanoparticles have a cubic crystal structure
with the d-values of magnetite being consistent with the
standard d-values listed in the X-ray powder JCPDS diffraction
data file.32
Surface Properties of the Magnetite Nanoparticles. The
surface properties of the magnetite nanoparticles are important
to enable design and tailoring of magnetic drug delivery systems
and magnetic resonance imaging contrast enhancement agents.
The Fe3O4 nanoparticles synthesized using the high-temperature
(32) Berry, L. G.; Thompson, R. M. X-ray diffraction data for minerals; Waverly
Press: New York, 1962; p 194.
6346 Langmuir, Vol. 23, No. 11, 2007 Zhang et al.

Figure 2. FTIR spectra of oleylamine and the hydrophobic Fe3O4

nanoparticles.
Table 2. Assignment of FTIR Spectra of Oleylamine and the
Hydrophobic Fe3O4 Nanoparticles Presented in Figure 2
IR absorption
samples bands/cm-1 descriptiona
Fe3O4 32,33 570, 375 The two bands at 570 and 375 cm-1
are characteristic absorption bands
of the Fe-O bond of bulk Fe3O4.
632, 585 The two bands at 632 and 585 cm-1
for nanoparticles Fe3O4 result
from split of the band at 570 cm-1
and shift to higher wavenumbers.
440 The band at 440 cm-1 for
nanoparticles Fe3O4 results
from the shifting of the 375 cm-1
band to a higher wavenumber.
oleylamine 3376, 3295 νas(NH2) and νs(NH2)
3004 ν(dC-H)
2925, 2853 νas(C-H) and νs(C-H)
1604, 795 δ(NH2)
1465 δ(CH3)
1071 ν(C-N)
722 ν(C-C)
hydrophobic 3434 ν(N-H···H)
Fe3O4
nanoparticles
2996 ν(dC-H)
2923, 2852 νas(C-H) and νs(C-H)
1609 δ(NH2)
1523 new absorption band f
formation of Fe-N bond
Figure 1. (a) Transmission electron micrograph of magnetite 1458, 1426 δas(CH3) and δs(CH3)
nanoparticles and (b) electron diffraction pattern. 1073 ν(C-N)
632, 585 absorption bands of the Fe-O bond
Table 1. Comparison of Experimental and Standard 441 absorption bands of the Fe-O bond
Interplanar Spacing (d) Values with Their Respective a
νs ) symmetric stretching vibration; νas ) asymmetric stretching
Diffracting Plane Index (h k l) in Fe3O4 Nanoparticles vibration; δ ) bending vibration.
d/nm d/nm hkl
phase experimental standard32 diffraction plane characterized by high surface activity; the atoms on the surface
Fe3O4 (cubic) 4.86 111 of nanoparticles tend to adsorb ions or molecules from the solution.
2.96 2.97 220 In the high-temperature decomposition reaction process adopted
2.53 2.53 311 here, iron acetylacetonate, 1,2-dodecanediol, oleic acid, and
2.10 2.10 400 oleylamine were used. Thus, to analyze the surface properties
1.71 1.71 422
1.61 1.62 511
of the Fe3O4 nanoparticles, FTIR studies of the hydrophobic
1.48 1.48 440 Fe3O4 nanoparticles were carried out. FTIR is an appropriate
1.33 620 technique to study the chemical adsorption or chemical interaction.
1.28 1.29 533 The FTIR spectra of oleylamine and the hydrophobic Fe3O4
1.21 1.21 444 nanoparticles are presented in Figure 2. The assignments of the
decomposition method are hydrophobic in character and can be characteristic FTIR absorption bands presented in Figure 2 are
conveniently dispersed into nonpolar or weakly polar hydrocarbon summarized in Table 2. The characteristic absorption bands for
solvent, such as hexane or toluene, to form a monodisperse Fe3O4 oleylamine mainly include νas(NH2) (3376 cm-1) and νs(NH2)
colloidal solution. Considering that there is a large surface-to- (3295 cm-1), ν(dCsH) (3004 cm-1), νas(CsH) and νs(CsH)
volume ratio and a number of unsaturated bonds on the surface (2925 cm-1, 2853 cm-1), δ(NH2) (1604 cm-1, 795 cm-1), and
of the Fe3O4 nanoparticles, the surface of the nanoparticles is ν(CsN) (1071 cm-1). On the basis of the assignment of the
Encapsulated Core-Shell Nanoparticles Langmuir, Vol. 23, No. 11, 2007 6347

Figure 3. FTIR spectra of the tetramethylammonium 11-aminoun-

decanoate surfactant and the hydrophilic Fe3O4 nanoparticles which
were transformed from hydrophobic Fe3O4 nanoparticles using the
tetramethylammonium 11-aminoundecanoate surfactant.

FTIR spectra of bulk and nanoparticles Fe3O4 reported in the

literature,33,34 the characteristic absorption bands of the hydro-
phobic Fe3O4 nanoparticles at 632, 585, and 441 cm-1 can be
attributed to Fe-O bonds. The two bands at 632 and 585 cm-1
are a consequence of the split of the absorption band of the
Fe-O bond of bulk Fe3O4 at 570 cm-1 that shifts to a higher Figure 4. FTIR spectra of (a) dextran, (b) 4-nitrophenyl chloro-
wavenumber. Similarly, the band at 441 cm-1 comes from another formate-activated dextran, (c) poly(NIPAAm-co-DMAAm) with an
absorption band of the Fe-O bond of bulk Fe3O4 at 375 cm-1, amino end group, and (d) dextran-g-poly(NIPAAm-co-DMAAm)
which also shifts to a higher wavenumber. It should be pointed polymer.
out that the reason for the shift of the absorption band of Fe-O
bonds of nanoparticles to higher wavenumbers is unclear now. 629, 596, and 441 nm belong to vibrations of the FesO bonds,
We can draw the following conclusions from Figure 2: while the characteristic absorption bands of the tetramethylam-
monium 11-aminoundecanoate mainly include νas(NH2) (3348
(a) The characteristic absorption bands of oleylamine at 2996
cm-1), νas(CsH), and νs(CsH) (2922 cm-1, 2850 cm-1). The
cm-1 (ν(dCsH)), 2923, 2852 cm-1 (νas(CsH) and νs(CsH)),
absorption bands at 1567 and 1488 cm-1 are in agreement with
1609 cm-1 (δ(NH2)), and 1073 cm-1 (ν(CsN)) are observed on
and correspond to free tetramethylammonium 11-aminounde-
the surface of hydrophobic Fe3O4 nanoparticles, while the two
canoate, implying the existence of the free -COO- group on the
characteristic absorption bands of oleylamine at 3376 to 3295
surface of the hydrophilic Fe3O4 nanoparticles.31 On the other
cm-1 are assigned to νas(NH2) and νs(NH2). Moreover, the
hand, the absorption band at 2347 cm-1 suggests that there is
absorption band at 3434 cm-1 was broadened due to the interaction
a -NH3+ group on the surface of the hydrophilic Fe3O4
of hydrogen bonds. This implies that oleylamine molecules were
nanoparticles. These hydrophilic groups render the previously
adsorbed on the surface of the Fe3O4 nanoparticles.
hydrophobic Fe3O4 nanoparticles to be redispersed in aqueous
(b) A new absorption band at 1523 cm-1 is attributed to
solution.
characteristic absorption of FesN bonds. It is suggested that
-NH2 coordinates with Fe(III) on the surface of the particles, FTIR Analysis of the Smart Polymer. PNIPAAm-based
consistent with ref 31. polymers and dextran-based polymers are expected to enable
aqueous loading of anticancer drugs and modulate drug release
(c) The three bands at 632, 585, and 440 cm-1 relate to FesO
in response to temperature change, while the latter, a natural
bonds in Fe3O4 nanoparticles. The aforementioned FTIR
polysaccharide, is biocompatible and enzymatically degrad-
observations imply that Fe3O4 nanoparticles are stabilized and
able.35-38 Dextran-g-poly(NIPAAm-co-DMAAm) smart polymer
functionalized by oleylamine.
includes the advantages of biocompatibility and enzymatic
Figure 3 is the FTIR spectra of the tetramethylammonium
degradation and improves the disadvantage of nonbiodegradability
11-aminoundecanoate surfactant and the hydrophilic Fe3O4
of the PNIPAAm-based polymers and the lack of stimuli-
nanoparticles which was transformed from hydrophobic Fe3O4
responsiveness of dextran-based polymers.
nanoparticles using the tetramethylammonium 11-aminounde-
The FTIR spectra in Figure 4 and assignments of their
canoate surfactant. Upon comparison of the spectrum of the
characteristic absorption bands listed in Table 3 confirm that the
surfactant with that of the hydrophilic Fe3O4 nanoparticles, we
dextran-g-poly(NIPAAm-co-DMAAm) smart polymer was syn-
observe that the tetramethylammonium 11-aminoundecanoate
thesized. Comparing with FTIR spectra of dextran (Figure 4a)
surfactant is adsorbed on the surface of the hydrophobic Fe3O4
and 4-nitrophenyl chloroformate-activated dextran (Figure 4b),
nanoparticles, because the characteristic absorption bands of
we see that the characteristic absorption bands of 4-nitrophenyl
Fe3O4 nanoparticles and tetramethylammonium 11-aminoun-
decanoate are observed. For example, the absorption bands at
(35) Huang, X.; Lowe, T. L. Biomacromolecules 2005, 6, 2131.
(36) Lemarchand, C.; Gref, R.; Couvreur, P. Eur. J. Pharm. Biopharm. 2004,
(33) Yamaura, M.; Camilo, R. L.; Sampaio, L. C.; Macêdo, M. A.; Nakamura, 58, 327.
M.; Toma, H. E. J. Magn. Magn. Mater. 2004, 279, 210. (37) Xu, X. Q.; Shen, H.; Xu, J. R. Appl. Surf. Sci. 2005, 252, 494.
(34) Ma, M.; Zhang, Y.; Yu, W.; Shen, H. Y.; Zhang, H. Q. Gu, N. Colloids (38) Lu, D. N.; Liu, Z. X.; Zhang, M. L.; Wang, X. G.; Liu, Z. Biochem. Eng.
Surf., A 2003, 212, 219. J. 2006, 27, 336.
6348 Langmuir, Vol. 23, No. 11, 2007 Zhang et al.

Table 3. Assignment of FTIR Spectra of Dextran, 4-Nitrophenyl Chloroformate-Activated Dextran, and Poly(NIPAAm-co-DMAAm)
with an Amino End Group Presented in Figure 4
IR absorption
sample bands/cm-1 descriptiona
dextran 3700-3200 ν(H-O···H)
2926, 2897 ν(C-H) of -CH2
1639 δ(CH3)
1460, 1356 δ(H-C-OH)
1262 ν(C-O-CH2-)
1157, 846 νas(C-O-C) and νs(C-O-C)
1016 δ(O-H)
4-nitrophenyl 3700-3200 ν(H-O···H)
chloroformate-activated
dextran
2925, 2897 ν(C-H) of -CH2
1806 (i) ν(CdO)
1636 δ(CH3)
1461 δ(H-C-OH)
1523 (ii), 1341 (iii) νas(NdO) and νs(NdO)
1266 ν(C-O-CH2-)
1153, 852 νas(C-O-C) and νs(C-O-C)
1016 δ(O-H)
952 (iv) ν(C-N)
poly(NIPAAm-co-DMAAm) 3444, 3311 ν(N-H···H)
with an amino end group
2972, 2932, 2868 νas(C-H) and νs(C-H) of -CH3 and -CH2
1648 ν(CdO)
1543 δ(N-H)
1460 δ(H-C-OH)
1261 ν(C-O-CH2-)
660-600 ν(C-S)
dextran-g-poly(NIAAm-co- 3435 ν(O-H) and ν(N-H)
DMAAm) polymer
2971, 2929, 2871 νas(C-H) and νs(C-H)
1638 δ(CH3)
1542 δ(N-H)
1265 ν(C-O-CH2-)
1020 δ(O-H)
660-600 ν(C-S)
a
νs ) symmetric stretching vibration; νas ) asymmetric stretching vibration; δ ) bending vibration or deformation.

Upon reaction between the poly(NIPAAm-co-DMAAm) with

Figure 5. Determination of lower critical solution temperature
(LCST).
chloroformate group are as follows: (i) (ν(CdO), 1806 cm-1),
(ii) (νas(NdO), 1523 cm-1), (iii) (νs(NdO), 1341 cm-1), and
(iv) (ν(CsN), 952 cm-1) in Figure 4b. This confirms that the
aim of obtaining 4-nitrophenyl chloroformate-activated dextran
was successful. The characteristic absorption bands of FTIR
spectra of poly(NIPAAm-co-DMAAm) with an amino end group
(Figure 4c) include ν(NsH) (3444, 3311 cm-1), ν(CdO) (1648
cm-1), δ(NsH) (1543 cm-1), and ν(CsS) (660-600 cm-1).
an amino end group and the 4-nitrophenyl chloroformate-activated
dextran, the characteristic absorption bands of the -NH2 (3444,
3311 cm-1) of the polymer and the 4-nitrophenyl chloroformate
group (the absorption bands identified as (i), (ii), (iii), and (iv)
in Figure 4) are not observed in Figure 4d. However, the main
characteristic absorption bands corresponding to dextran at 3700-
3200 cm-1 (ν(HsO‚‚‚H)) and 1020 cm-1 (δ(OsH)) and from
the poly(NIPAAm-co-DMAAm) at 2971, 2929, and 2871 cm-1
(νas(CsH) and νs(CsH) of -CH3 and -CH2), 1542 cm-1 (δ-
(NsH)), and 660-600 cm-1 (ν(CsS)) are observed in Figure
4d. These observations confirm the successful synthesis of the
dextran-g-poly(NIPAAm-co-DMAAm) smart polymer.
Determination of LCST of the Smart Polymer. The LCST
of aqueous solution of the dextran-g-poly(NIPAAm-co-DMAAm)
smart polymer containing 5 wt % of PBS solution (pH 7.4) was
determined by transmittance of 500 nm visble light (Figure 5).
The smart polymer exhibited the desired LCST of ∼38 °C, which
is above body temperature, because of the hydrophilic contribution
of DMAAm as a comonomer. This means that the smart polymer
hydrates and forms an expanded structure below the LCST, while
it dehydrates and forms a compact structure above the LCST.
It should be pointed out that the smart polymer has a branched
molecular architecture that may result in a micellization-type
aggregation mechanism,39-42 which is reflected by the broadening
(39) Laschewsky, A.; Relkai, El D.; Wischerhoff, E. Macromol. Chem. Phys
2001, 202, 276.
(40) Bokias, G.; Hourdet, D.; Iliopoulos, I. Macromolecules 2000, 33, 2929.
(41) Virtanen, J.; Baron, C.; Tenhu, M. Macromolecules 2000, 33, 336.
Encapsulated Core-Shell Nanoparticles
Figure 6. Transmission electron micrograph of magnetite nano-
particles encapsulated with dextran-g-poly(NIPAAm-co-DMAAm)
smart polymer.
of the temperature range, as observed in Figure 5. Thus, as a
carrier, such a biodegradable smart polymer with a triggering
mechanism of temperature response is especially suitable for a
controlled drug release system.
Characterization of the Fe3O4 Nanoparticles Coated with
the Smart Polymer. Magnetic nanoparticles for drug delivery
systems and magnetic resonance imaging are required to be
encapsulated with a polymer to form capsules with a core-shell
structure. In our case, the capsules with core-shell structure are
characterized by the hydrophilic Fe3O4 magnetic core encap-
sulated with a shell consisting of the dextran-g-poly(NIPAAm-
co-DMAAm) smart polymer with characteristics of thermosen-
sitivity, biodegradability, and hydrophility. In Figure 6, low-
magnification and high-magnification transmission electron
(42) Rackaitis, K.; Strawwhecker; Manias, E. J. Polym. Sci., Part B: Polym.
Phys. 2002, 40, 2339.
Langmuir, Vol. 23, No. 11, 2007 6349
Figure 7. A comparison of FTIR spectra of magnetite nanoparticles
coated with smart polymer and pure smart polymer.
Figure 8. Optical photograph of the magnetic nanocapsules attracted
by a magnet.
micrographs of the Fe3O4 nanoparticles coated with dextran-g-
poly(NIPAAm-co-DMAAm) smart polymer are presented. Figure
6 confirms that the magnetic Fe3O4 nanoparticles coated with
smart polymer are nanocapsules of spherical shape with an average
diameter of ∼8 nm. On encapsulation with polymer, the size of
the nanocapsules is increased from 5 to 8 nm. This is an indirect
confirmation of the encapsulation of Fe3O4 magnetic core with
a ∼3 nm thick polymer shell. To directly confirm the evidence
of the smart polymer on the surface of Fe3O4, FTIR studies were
carried out in a manner similar to that described above. In Figure
7, a comparison of FTIR spectra of Fe3O4 nanoparticles coated
with smart polymer and pure smart polymer is presented. Their
spectra are almost same with the exception of the absorption
bands of the -NH3+ at 2365 and 2341 cm-1 from the surfactant
on the hydrophilic Fe3O4 nanoparticles. In addition, the absorption
bands of the -OH and -NH2 groups range from 3200 to 3700
cm-1 and as expected broaden and shift to the lower wavenumber,
which results from hydrogen bond interaction. This observation
confirms the existence of the smart polymer coated on the
hydrophilic Fe3O4 nanoparticles and also implies Van der Waals
force and hydrogen bond type interaction between polymer and
magnetite nanoparticles.
6350 Langmuir, Vol. 23, No. 11, 2007
Scheme 2. Schematic Illustration of the Synthesis of Magnetic Carrier Coated with Smart Polymer
Magnetic capsules coated with polymers generally exhibit a
lower value of magnetization. The lower value is related to the
overall reduction in the total ferrite content in the coated core-
shell nanoparticles which gets reduced upon coating with polymer.
Detailed magnetic behavior of polymer-coated magnetic ferrites
has been studied by us on previous occasions43,44 and is not
discussed here, because it does not contribute the objective.
Also, the magnetic behavior of ferrites has been extensively
discussed in the literature. However, we present here a simple
experiment to examine the retention of magnetism in magnetic
capsules coated with smart polymer. In Figure 8, an optical
photograph of the magnetic capsules attracted by an external
(43) Nathani, H.; Gubbala, S.; Misra, R. D. K. Mater. Sci. Eng., B 2004, 111,
95.
(44) Nathani, H.; Misra, R. D. K. Mater. Sci. Eng., B 2004, 113, 228.
Zhang et al.
magnet is presented. Upon application of an external magnetic
field to the bottle filled with the magnetic capsules, the
nanocapsules were attached on the side of the bottle that was
in close proximity to the magnet, and the dispersion was clear
and transparent. Removal of the external magnetic field and
redispersion by sonication led to the recovery of this dispersion,
implying that the magnetic capsules retained magnetism on
incorporated with polymer. On the basis of analyses of the
above experimental results, the concept of synthesis and the
schematic illustration of the experimental procedure of magnetic
carrier coated with smart polymer is schematically depicted in
Scheme 2.
We are now currently studying the drug release response and
intercellular uptake of drug which will be reported in a followup
paper.
Encapsulated Core-Shell Nanoparticles
Conclusion
In this study, a novel temperature-sensitive grafted biopolymer
with a LCST of ∼38 °C, dextran grafted with poly(N-
isopropylacrylamide-co-N,N-dimethylacrylamide) [dextran-g-
poly(NIPAAm-co-DMAAm)], was successfully coated on the
surface of hydrophilic magnetite nanoparticles to form a core-
shell structure by cross-linking and intermolecular interaction.
The morphology of composite core-shell nanoparticles was
spherical with a diameter of ∼8 nm. FTIR studies confirmed the
appropriateness of the envisaged carrier characterized by a
magnetic Fe3O4 core and a dextran-g-poly(NIPAAm-co-
Langmuir, Vol. 23, No. 11, 2007 6351
DMAAm) shell. The unique and novel carrier combines the
stimuli-responsive and biodegradable properties of the smart
polymer with the advantages of magnetic Fe3O4 nanoparticles,
having potential applications in a magnetic drug-targeting delivery
system for controlled drug release and contrast enhancement of
magnetic resonance imaging.
Acknowledgment. The financial support for the work
presented here was obtained from CSFM.
LA0636199